Cholecystokinin receptor A gene polymorphism in gallstone disease and gallbladder cancer

Background and Aim:  Gallbladder carcinoma (GBC) usually arises in the background of gallstone disease which may be causatively related to decreased gallbladder contractility. Cholecystokinin receptor A ( CCK-AR ) mediates signals resulting in gallbladder contraction. Deteriorating gallbladder contraction promotes gallstone formation. A common genetic polymorphism of CCK-AR may be causatively associated with the risk of gallstone and GBC. This study aimed to understand the association of CCK-AR Pst I polymorphism in gallstone disease with gallbladder cancer.
Method:  This study included 165 gallstone patients, 139 GBC patients, and 190 healthy subjects. Genotyping was done using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.
Results:  The frequency of the A1A1 genotype of CCK-AR was significantly higher in gallstone patients than healthy individuals ( P  = 0.008 odds ratio [OR] = 2.25, and 95% confidence interval [CI]:1.2–4.1). However, there was a significant difference in the frequency of A1A1 genotype when gallstone patients were compared to GBC patients ( P  = 0.041, OR = 0.49, and 95% CI: 0.3–0.9). On stratification of GBC patients according to presence or absence of gallstones, GBC patients without stones were compared to controls and GBC patients with stones were compared to stone patients; however, no significant differences in frequencies were observed.
Conclusion:  The results suggest that the A1A1 genotype of CCK-AR is an independent genetic risk factor for gallstone disease and does not modulate the susceptibility of gallbladder cancer.     

Cholecystectomy improves long-term success after endoscopic treatment of CBD stones

BACKGROUND/AIMS: The aim was to study prospectively primary endoscopic treatment of CBD stones and further the long-term need for renewed gallstone disease interventions, defined as short- and long-term outcome. METHODOLOGY: Seven years prospective follow-up of 101 consecutive patients with CBD stones who underwent endoscopic treatment with the intent of primarily achieving duct clearance. RESULTS: Many patients underwent several endoscopy sessions before stone clearance was completed in 83%. Eleven patients were treated surgically, 2 patients received a permanent stent, and the remaining 3 became stone free with other means. Complications occurred in 47 patients. During follow-up, 31 patients were readmitted for gallstone disease and 15 of these had recurrent CBD stones. Ten percent (8/78) of patients with the gallbladder in situ had acute cholecystitis during follow-up and late cholecystectomy was carried out in 22%. Risk factors for new gallstone disease were an in situ gallbladder containing stones and previous episodes of CBD stones. CONCLUSIONS: A goal of complete CBD stone clearance with ERC and ES proved to be relatively resource consuming. Subsequent cholecystectomy after duct clearance for CBD should be advised when the gallbladder lodges gallstones, especially in younger patients. Recurrent CBD stones were not influenced by cholecystectomy.     

Gallbladder function during gallstone dissolution. Effect of bile acid therapy in patients with gallstones

Impaired gallbladder emptying has been associated with gallstone disease but any effect on or from bile acid therapy for gallstone dissolution is unknown. We evaluated gallbladder filling and emptying with low-dose cholecystokinin infusion (0.02 U/kg.h) by computer-assisted cholescintigraphy in 52 controls versus 31 gallstone patients: 17 treated with 12-15 mg/kg.day of chenodeoxycholic acid and 14 with 8-10 mg/kg.day of ursodeoxycholic acid. Thirteen of 31 patients with complete dissolution had four scans: before, after 3 mo of therapy, after stone dissolution, and after discontinuation of bile acids. The 18 failures had three scans: before and after 3 and 15-18 mo of therapy. Before therapy, the 31 gallstone patients had significantly impaired gallbladder emptying compared with controls, but filling was not decreased. Bile acids significantly decreased emptying in both treatment groups after 3 mo of therapy. In the dissolution group, emptying improved once the stones had dissolved and increased further upon discontinuing the bile acids. In the failures, impaired emptying persisted for up to 15-18 mo. Gallbladder filling in the 31 gallstone patients was also significantly decreased after 3 mo of bile acid therapy, particularly in the failure patients, 5 of whom exhibited zero filling. No differences were detected between ursodeoxycholic acid and chenodeoxycholic acid for either gallbladder function or efficiency of dissolution. Thus, bile acid therapy impairs gallbladder filling and emptying in gallstone patients. Gallstone dissolution improves emptying, which is further enhanced when bile acids are discontinued.     

Interventional radiology in gallstone disease

Interventional radiologic techniques for the treatment of gallstone disease are becoming more widely available. Percutaneous cholecystostomy [corrected] can be lifesaving in critically ill elderly patients who have acute cholecystitis. Contact dissolution of stones with methyl tert-butyl ether and percutaneous extraction (with or without fragmentation) of calculi are treatment options in patients who are at high risk for surgery or who do not desire an operation. With increasing use of intracorporeal gallstone lithotripsy techniques in the gallbladder and bile ducts, combined fluoroscopic and direct visualization during percutaneous procedures is becoming more important. Percutaneous chemical ablation of the gallbladder offers a potential solution to the problem of gallstone recurrence.     

Bile composition, microspheroliths, antinucleating activity, and gallstone calcification.

This study examined if abnormalities in bile composition and antinucleating activity are associated with gallstone calcification. Nineteen controls without gallbladder disease and 42 patients with cholesterol stones were studied. Bile was obtained at surgery and analyzed for pH and PCO2, ionized calcium, and total calcium. The pH and carbonate concentrations of gallbladder bile were significantly higher in patients with calcified stones than in patients with noncalcified stones and in controls, resulting in significantly higher levels of the ion product in patients with calcified gallstones. Microspheroliths of calcium carbonate, seen on microscopic examination of bile, predicted stone calcification with a sensitivity of 86%, a specificity of 86%, and a predictive value of 86%. Bile from control subjects completely inhibited precipitation of calcium carbonate from a supersaturated solution, whereas bile from subjects with calcified and noncalcified gallstones did not. It is concluded that gallstone calcification is related to elevated bile pH and carbonate concentrations, resulting in an elevated ion production of calcium carbonate in gallbladder bile. In addition, bile from subjects with calcified and noncalcified gallstones lacks antinucleating activity for calcium carbonate.     

Ultrasonographic screening for gallstone disease in middle-aged women. Detection rate, symptoms, and biochemical features

Five hundred and forty-seven middle-aged women, selected at random from the population of Malm?, Sweden, were invited to a screening survey for gallstone disease; 424 participated (77.5%). Forty-one had previously been operated on for gallbladder disease. The prevalence of gallstone disease, on the basis of a positive finding at ultrasonography and cholecystography, was 11%. The predictive value of a positive finding at ultrasonography was 86%. Six out of 10 women with gallstone were classified as asymptomatic. Body weight, blood pressure, liver enzymes, fasting blood glucose, and blood lipids, including apolipoprotein-A, did not differ significantly in women with and without gallstone disease. At least 9 out of 10 gallstones appeared to be cholesterol stones. Approximately half were of a size that would make them accessible for dissolution therapy.     

Cholesterol and pigment gallstone disease: comparison of the reliability of three bile tests for differentiation between the two stone types

Gallbladder biles and stones were obtained at 116 cholecystectomies for symptomatic gallstone disease. All 33 patients younger than 50 years had cholesterol stones, whereas 40% of the older patients had pigment stones. We compared the reliability of three different bile tests for the differentiation between cholesterol and pigment stone patients. Whereas both the presence of cholesterol monohydrate crystals in fresh gallbladder bile and a nucleation time less than or equal to 20 days in ultrafiltered gallbladder bile had a specificity of 100% for cholesterol gallstone disease, biliary supersaturation with cholesterol (cholesterol saturation index greater than 1.0) had a low specificity. The sensitivity of nucleation time less than or equal to 20 days for cholesterol gallstone disease was 78% in concentrated gallbladder biles (biliary total lipid concentration greater than or equal to 5 g/dl) but only 21% in dilute biles (biliary total lipid concentration less than 5 g/dl). In contrast, examination for the presence of cholesterol crystals in fresh bile was reasonably sensitive both in concentrated and dilute gallbladder biles (sensitivity, 84% and 72%, respectively). In addition, duodenal bile obtained from 16 patients (10 cholesterol, 6 pigment) before cholecystectomy showed cholesterol crystals in 7 of the cholesterol but in none of the pigment stone patients. We conclude that examination of fresh bile for cholesterol crystals is a specific and reasonably sensitive test for cholesterol gallstone disease.     

Therapy of gallstone disease: What it was, what it is, what it will be

Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic factors.Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones.The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol gallstones.In this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis.     

Gallstone disease: Current therapeutic practice

Opinion statement Most asymptomatic gallstone carriers require no therapy. Laparoscopic cholecystectomy is the best definitive therapy for symptomatic gallstone disease. Selective laparoscopic cholecystectomy can provide secondary prevention of symptoms and complications in certain instances (in a complex clinical setting such as sickle cell disease or to prevent gallbladder carcinoma from developing in those at risk with large [> 3 cm] gallstones or with a calcified gallbladder). Primary prevention is unproven but focuses on early identification and risk alteration to decrease the possibility of developing gallstones. Ursodeoxycholic acid has a limited role for stone dissolution but can prevent stone development in severe obesity during rapid weight reduction with diet or after bariatric surgery. Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy represents the therapeutic cornerstone for managing severe pancreatitis and cholangitis.     

Mechanisms of disease: the genetic epidemiology of gallbladder stones

Cholelithiasis is one of the most prevalent and most expensive gastroenterologic diseases. It belongs to the group of complex metabolic disorders that affect humans, and its critical pathogenic mechanisms are not well defined. As a result, primary or secondary prevention strategies are sparse, and the only effective treatment is cholecystectomy. Here we provide an update on the molecular pathogenesis of gallbladder stones, evidence supporting the hypothesis that genetic factors are key elements predisposing to gallstones, and progress in human genetic studies of cholesterol stones. Data from recent identical twin, family and linkage studies provide conclusive evidence for a strong genetic component to gallstone disease. Furthermore, epidemiologic studies in at-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. By contrast, monogenic subtypes of cholelithiasis, such as ATP-binding-cassette transporter deficiencies, appear to be rare. The summary of human association studies illustrates that distinct common gene variants might contribute to gallstone formation in different ethnic groups. The characterization of lithogenic genes in knockout and transgenic mice and the identification of many gallstone-susceptibility loci in inbred mice provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal novel molecular targets for prevention and medical therapies.     

Measurement of calcium content of gallstones by computed tomography and the relationship between gallbladder function and calcification of gallstones

To evaluate the relationship between gallbladder function and calcification of gallstones, we studied gallbladder contractility by oral cholecystography, the computed tomography (CT) number of stones for 30 gallstone patients, calcium content of 13 stones operatively extirpated, and the degree of inflammatory change in 13 surgical gallbladder specimens. There was significant correlation between the calcium content and CT numbers of stones, and 1% of the calcium content of gallstone was approximately equal to 40 Hounsfield Units (HU) of the CT number. The calcium content of stones in patients with normal gallbladder contractility was extrapolated to be below 1.5%, while that with poor contractility ranged from 0% to 21%. Additionally there is a possibility that calcium content increases, related to the inflammatory change of gallbladder. Hence our results suggested that measurement of the CT number of stones is useful to evaluate the calcium content of gallstones, and that the gallbladder contractility could be one of the factors to influence calcification of stones.     

Development of a hybrid percutaneous-endoscopic approach for the complete clearance of gallstones

Cholecystitis is common and costly to the health care system. Cholecystectomy is curative and the treatment of choice. Alternatives to cholecystectomy, however, are needed for patients who cannot undergo this surgery. However, procedures such as percutaneous cholecystostomy, endoscopic transpapillary and transduodenal gallbladder drainage, and dissolution therapy have limitations such as continued gallstone burden. More effective and minimally invasive alternatives, therefore, are needed. We developed a hybrid percutaneous-endoscopic approach for complete gallstone clearance in an elderly patient who was not a candidate for surgery. If replicated and proven to be safe, this technique could be a minimally invasive alternative to cholecystectomy for patients with symptomatic gallstone disease who are not good candidates for surgery.     

Measurement of calcium content of gallstones by computed tomography and the relationship between gallbladder function and calcification of gallstones

To evaluate the relationship between gallbladder function and calcification of gallstones, we studied gallbladder contractility by oral cholecystography, the computed tomography (CT) number of stones for 30 gallstone patients, calcium content of 13 stones operatively extirpated, and the degree of inflammatory change in 13 surgical gallbladder specimens. There was significant correlation between the calcium content and CT numbers of stones, and 1% of the calcium content of gallstone was approximately equal to 40 Hounsfield Units (HU) of the CT number. The calcium content of stones in patients with normal gallbladder contractility was extrapolated to be below 1.5%, while that with poor contractility ranged from 0% to 21%. Additionally there is a possibility that calcium content increases, related to the inflammatory change of gallbladder. Hence our results suggested that measurement of the CT number of stones is useful to evaluate the calcium content of gallstones, and that the gallbladder contractility could be one of the factors to influence calcification of stones.     

Gallbladder stones: Shockwave therapy

Within the past 7 years, gallbladder lithotripsy by shockwaves has been proven to be a safe and effective non-invasive therapy for selected patients with gallstone disease. While regulatory decisions prevent shockwave therapy from being used more frequently in the USA, the number of patients treated in Europe and Asia is increasing constantly. At our institution, a relatively constant number of about 250 new patients per year have been treated since 1988 (Figure 4).About 20% of patients with gallstones are suitable for shockwave therapy according to present criteria. The rate of evacuation of all fragments is determined by the initial stone number and stone size, the success at stone fragmentation, adjuvant bile acid dissolution therapy, and gallbladder contractility. In contrast to laparoscopic cholecystectomy (Dubois et al, 1989; Perissat et al, 1989; Southern Surgeons Club, 1991), shockwave therapy does not require general anaesthesia. And in contrast to direct contact dissolution therapy of gallbladder stones using MTBE (Thistle et al, 1989), lithotripsy is non-invasive. In the majority of patients, complete fragment disappearance takes several months. Preliminary analyses of the cost-effectiveness of lithotripsy have revealed that lithotripsy, including retreatments and bile acid medication for recurrent stones, costs about as much as open cholecystectomy (Rothschild et al, 1990; Bass et al, 1991).     

The ultrasound survey of gallstone diseases of patients infected with Clonorchis sinensis in southern Taiwan

Ultrasonography was used to evaluate the relationship between the gallstone diseases and infection with Clonorchis sinensis. One thousand and ninety-one Hakkanese in southern Taiwan were examined in the past 2 years. Among the 947 cases infected with clonorchiasis, 89 cases were found to have gallstone diseases, which included gallbladder stones (85 cases), common bile duct stones (three cases) and one case of intrahepatic duct stone, indicating a prevalence of 8.97, 0.32 and 0.11% respectively. The overall prevalence of gallstones in the infected group was 9.39%. In the other 144 cases without clonorchiasis infection, eight patients were found to have gallstone disease, which included gallbladder stone (six cases) and intrahepatic duct stone (two cases), indicating an incidence of gallstone of 4.16 and 1.39% respectively. The overall prevalence of gallstones in the non-infected group was 5.56%. A comparison between the infected and non-infected groups was made and showed no significant relationship between gallstone disease and clonorchiasis.     

Epidemiology of gallbladder disease: cholelithiasis and cancer

Diseases of the gallbladder are common and costly. The best epidemiological screening method to accurately determine point prevalence of gallstone disease is ultrasonography. Many risk factors for cholesterol gallstone formation are not modifiable such as ethnic background, increasing age, female gender and family history or genetics. Conversely, the modifiable risks for cholesterol gallstones are obesity, rapid weight loss and a sedentary lifestyle. The rising epidemic of obesity and the metabolic syndrome predicts an escalation of cholesterol gallstone frequency. Risk factors for biliary sludge include pregnancy, drugs like ceftiaxone, octreotide and thiazide diuretics, and total parenteral nutrition or fasting. Diseases like cirrhosis, chronic hemolysis and ileal Crohn's disease are risk factors for black pigment stones. Gallstone disease in childhood, once considered rare, has become increasingly recognized with similar risk factors as those in adults, particularly obesity. Gallbladder cancer is uncommon in developed countries. In the U.S., it accounts for only ~ 5,000 cases per year. Elsewhere, high incidence rates occur in North and South American Indians. Other than ethnicity and female gender, additional risk factors for gallbladder cancer include cholelithiasis, advancing age, chronic inflammatory conditions affecting the gallbladder, congenital biliary abnormalities, and diagnostic confusion over gallbladder polyps.     

Should elective endoscopic sphincterotomy replace cholecystectomy for the treatment of high-risk patients with gallstone pancreatitis?

Since the introduction of endoscopic sphincterotomy approximately 15 years ago, the indications for this procedure have expanded. Currently endoscopic sphincterotomy is the procedure of choice for management of retained common bile duct stones following cholecystectomy. It is also being used more frequently for choledocholithiasis with an intact gallbladder in high-risk patients and in some patients with acute gallstone pancreatitis. In patients recovering from an episode of gallstone pancreatitis, standard practice has been subsequent cholecystectomy with possible exploration of the common bile duct. To avoid surgery in high-risk patients, we propose that an elective endoscopic sphincterotomy may be a reasonable therapeutic option regardless of whether common bile duct stones are present at the time of ERCP. A prospective trial is needed to examine this issue since to date there is no literature on endoscopic sphincterotomy in the absence of choledocholithiasis for gallstone pancreatitis in patients with intact gallbladders.     

Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy

The E4 allele of apolipoprotein E (apoE4) has previously been associated with symptomatic gallstone disease. The aim of this study was to determine if apoE4 is associated with the development of gallbladder sludge and/or stones during pregnancy. We conducted a nested case-control study based on an ongoing cohort study of gallbladder disease in pregnancy. Women in this study receive gallbladder ultrasounds in each trimester of pregnancy. Cases (n = 52) were defined as women with incident gallbladder sludge or stones diagnosed at the third trimester ultrasound. Controls (n = 104) were defined as women without gallbladder sludge or stones on any of 3 study ultrasounds. ApoE genotyping was performed from stored white blood cell pellets. Data were analyzed by stratified analysis and multivariate logistic regression. Cases and controls were similar in baseline characteristics. Forty-two women had sludge, 6 had gallstones, and 4 had both sludge and stones. After adjusting for risk factors such as age, parity, and body mass index, the odds ratio (OR) for the association between heterozygosity or homozygosity for the apoE4 allele and incident gallbladder sludge or stones was 0.91 (95% confidence interval [CI], 0.41-2.02). Further adjustment for family medical history and serum lipid levels did not substantially change these results (OR, 0.73; 95% CI, 0.29-1.82). In conclusion, apoE4 appears to have little or no overall association with the development of new gallbladder sludge or stones in pregnancy. However, an effect could not be ruled out in certain subgroups, such as blacks or women who are homozygous for apoE4.     

Factors affecting gallstone recurrence after successful extracorporeal shock wave lithotripsy

Ninety-six patients treated successively for symptomatic cholelithiasis with extracorporeal shock wave lithotripsy (ESWL) and oral bile acid therapy consisting of ursodeoxycholic acid in daily dosages of 600 mg were prospectively followed for gallstone recurrence for a median of 13 months. Ultrasonography was performed to detect stone recurrence at 3, 6, and 12 months, and then yearly after the termination of therapy. Recurrent stones were found in 17 patients (18%). The cumulative probability of gallstone recurrence was 15.8% at 12 months, 26.1% at 24 months, and 30.7% at 36 months. The probability of stone recurrence over the entire period of observation was not dependent on stone number, whereas the median interval to detection of recurrence was significantly shorter in the patients with multiple stones (2 months) than in those with solitary stones (8 months) (p < 0.05). The rate of impaired gallbladder contractility was higher in patients with recurrence (8/15, 53.3%) when compared with those with no recurrence (15/72, 20.8%) (p < 0.01). Neither age, gender, or stone characteristics predicted stone recurrence. Only one patient with a recurrence reported biliary pain. Of the 15 patients with recurrent stones who opted for further nonsurgical treatment, complete stone disappearance was achieved in 10. Impaired gallbladder function may predict gallstone recurrence after ESWL.